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BACKGROUND: The risk of primary aristolochic acid (AA)-associated urothelial carcinoma (AA-UC) has been summarized by a 2013-published meta-analysis. Given that additional evidence has been continuously reported by original studies, an updated meta-analysis is needed. Meanwhile, to complete the whole picture, a systematic review of molecular alterations observed in AA-urinary tract cancers (AA-UTC) was also performed. METHODS: We searched PubMed, Embase and four Chinese databases up to October 2020. Observational studies comparing risk or oncologic outcomes of UTC between patients with and without AA exposure were eligible for systematic review and meta-analysis. Studies investigating molecular alterations in AA-UTC using human tissue samples were eligible for systematic review. RESULTS: In total, 38 and 20 studies were included in the systematic review and meta-analysis, respectively. Exposure to AA led to an overall increased risks of primary UTC [UC and renal cell carcinoma (RCC)] (OR 6.085, 95% CI 3.045-12.160) and postoperatively recurrent UC (RR 1.831, 95% CI 1.528-2.194). Subgroup analysis of postoperative primary AA-upper tract UC (AA-UTUC) showed increased risks of bladder recurrence (adjusted RR 1.949, 95% CI 1.462-2.597) and contralateral UTUC recurrence (crude RR 3.760, 95% CI 2.225-6.353), worse overall survival (adjusted HR 2.025, 95% CI 1.432-2.865) and worse disease-specific survival (adjusted HR 3.061, 95% CI 1.190-7.872), but no effect on cancer-specific survival (adjusted HR 0.772, 95% CI 0.269-2.215). High mutation load with AA mutational signature presenting largely in the putative driver genes was observed in AA-UTUC. In contrast, AA mutational signature is rarely found in the mutated RCC driver genes and the mutation load in AA-RCC is low. Therefore, AA has different roles in the genesis of UTUC and RCC. CONCLUSIONS: Implementing effective strategies to completely protect people from exposure to AA is urgently needed. Additionally, more effort should be made in identifying the precise carcinogenic mechanisms of AA to determine the future treatment strategies. PLAIN LANGUAGE SUMMARY: Risk, recurrence and survival outcomes after surgery and molecular changes possibly involved in the genesis of aristolochic acid-associated urinary tract cancers Background: The association between aristolochic acid (AA) and primary urothelial carcinoma (UC) has been summarized by a 2013-published meta-analysis. Given that additional evidence has been reported in the past 7 years, an updated meta-analysis is needed. Meanwhile, to complete the whole picture, a systematic review of molecular changes possibly involved in AA-mediated urinary tract carcinogenesis was also performed. Methods: We searched PubMed, Embase and four Chinese databases for human studies up to October 2020. Studies comparing the risk of urinary tract cancer (UTC) between patients with and without AA exposure and studies investigating the molecular changes in AA-associated UTC (AA-UTC) using human tissue samples were eligible for inclusion. Thirty-eight studies were finally included. Results: The results showed that exposure to AA was associated with a 6-fold increased risk of primary UTC (UC and renal cell carcinoma, RCC) and a 1.8-fold increased risk of postoperatively recurrent UC. After studies reporting primary AA-upper tract UC (AA-UTUC) were analyzed, a 1.9-fold increased risk of bladder recurrence and a 3.8-fold increased risk of contralateral UTUC recurrence was observed. Additionally, exposure to AA worsened the postoperative survival of patients with UTUC by a 2-fold increased risk of overall death and a 3-fold increased risk of death from other diseases and recurrences. However, there was no effect on death due to cancer. Lastly, AA seemed to play different roles in the etiology of UTUC and RCC based on the observations of different mutation loads and different distributions of AA-induced mutations in AA-UTUC and AA-RCC samples. Conclusions: Implementing effective strategies to completely protect people from exposure to AA is urgently needed. Moreover, more effort should be made in identifying the precise carcinogenic mechanisms of AA-UTC to determine the future treatment strategies.
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OBJECTIVES: Objective structured clinical examinations (OSCEs) are common for formative assessment. We developed an Online Smart Communicative Education System and aimed to explore the factors that affect the perceptions of both teachers and students for teaching and learning. METHODS AND ANALYSIS: A two-year cross-sectional cohort study was undertaken. The program includes three parts. Part I Pre-OSCE: an online flipped class in preparation for task-related knowledge and skills. Part II OSCE-day: 10 tasks in one track formative OSCE. Part III Post-OSCE: extended online feedback for participants with further questions after the exam and raters with more feedback after reviewing their performance online. Principal component analysis with varimax rotation was performed to analyze the perceptions of students and teachers to the Online System by means of questionnaires. RESULTS: Seventy-six pharmacy students (male 32.9%) took the exam and 24 raters (male, 25%) participated in the scoring during the OSCEs. The mean G coefficient was 0.88. Seventy-six questionnaires from the students were obtained for the analysis. Results explained the cumulative variance of 73.9% for component (1) "Effects of extended online feedback": 40% and (2) "Facilitation of learning": 33.9%. Thirty-nine questionnaires from the raters who experienced the Online System were obtained for the analysis (male 23.1%). Results explained a cumulative variance of 77.3% for component (1) "Effects of extended online feedback": 36.6%, (2) "Facilitation of scoring and feedback": 24.5%, and (3) "Feasibility of online platform": 16.2%, respectively. CONCLUSION: We demonstrated good reliability for digitizing the scoring system with educational support to facilitate teaching. "Effects of extended online feedback" was the major aspect in explaining the variance from the perceptions of students and raters by factor analysis. In comparison with traditional formative OSCEs, extended online feedback is a novel approach, which extends the process of learning and teaching among the learners and raters and overcomes the barriers of time limitation and distance.
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PURPOSE: To report the unsafe herb-drug interactions between a commercial product of noni juice and phenytoin in a human case. CASE REPORT: A 49-year-old-male has been treated with phenytoin for epilepsy for more than ten years. In spite of his medication adherence, persistent sub-therapeutic phenytoin levels, which were sometimes from low to undetectable, with the result of having poor seizure control were noted as the noni fruit juice was co-administered daily. The possible mechanism is speculated to be due to noni juiceinduced cytochrome P-450 2C9 metabolism of phenytoin. Owing to many beneficial effects of noni juice, the patient was unwilling to accept our advice to quit taking it. Clobazam treatment was added, and with gradually reducing the amount of juice drunk over six months, the patient's epilepsy has been well controlled. Now only auras along with sometimes minor partial seizures occur, but no major attack has been reported for more than one year. CONCLUSION: Phenytoin had been commonly used for seizure control worldwide and nearly half of patients with epilepsy had received complementary and alternative medicine in Taiwan. Thus, this report is significantly important for clinicians to be aware of the interaction between antiepileptic drugs and some herbs like noni juice. Moreover, as far as we know, this is a rare human case that is reported to disclose this unfavorable herb-drug interaction.
